Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis

Abstract

Focal and segmental glomerulosclerosis1 (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding α-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant α-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type α-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: FSGS pedigrees and FSGS-1 locus.
Figure 2: Kidney biopsies.
Figure 3: Mutational analysis.
Figure 4: α-Actin sequence alignment.
Figure 5: Analysis of α-actinin-4 expression.
Figure 6: Actin-binding experiments.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Ichikawa, I. & Fogo, A. Focal segmental glomerulsoclerosis . Pediatr. Nephrol. 10, 374– 391 (1996).

    Article  CAS  Google Scholar 

  2. Honda, K. et al. Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. J. Cell. Biol. 140, 1383–1393 (1998); erratum: 143, 276 (1998).

    Article  CAS  Google Scholar 

  3. Mathis, B.J. et al. A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13: Rapid Communication. Kidney Int. 53, 282–286 (1998).

    Article  CAS  Google Scholar 

  4. Winn, M. et al. Linkage of a gene causing familial focal segmental glomerulosclerosis to chromosome 11 and further evidence of genetic heterogeneity. Genomics 58, 113–120 ( 1999).

    Article  CAS  Google Scholar 

  5. Fuchshuber, A. et al. Mapping a gene (SRN1) to chromosome 1q25–q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis . Hum. Mol. Genet. 4, 2155– 2158 (1995).

    Article  CAS  Google Scholar 

  6. Kestila, M. et al. Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol. Cell 1, 575–582 (1998).

    Article  CAS  Google Scholar 

  7. Drenckhahn, D. & Franke, R.P. Ultrastructural organization of contractile and cytoskeletal proteins in glomerular podocytes of chicken, rat, and man. Lab. Invest. 59, 673– 682 (1988).

    CAS  PubMed  Google Scholar 

  8. Smoyer, W.E., Mundel, P., Gupta, A. & Welsh, M.J. Podocyte α-actinin induction precedes foot process effacement in experimental nephrotic syndrome . Am. J. Physiol. 273, F150– 157 (1997).

    CAS  PubMed  Google Scholar 

  9. Shirato, I., Sakai, T., Kimura, K., Tomino, Y. & Kriz, W. Cytoskeletal changes in podocytes associated with foot process effacement in Masugi nephritis. Am. J. Pathol. 148, 1283–1296 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kurihara, H., Anderson, J.M. & Farquhar, M.G. Increased Tyr phosphorylation of ZO-1 during modification of tight junctions between glomerular foot processes. Am. J. Physiol. 268, F514–524 ( 1995).

    CAS  PubMed  Google Scholar 

  11. Djinovic-Carugo, K., Young, P., Gautel, M. & Saraste, M. Structure of the α-actinin rod: molecular basis for cross-linking of actin filaments. Cell 98, 537–546 ( 1999).

    Article  CAS  Google Scholar 

  12. Beggs, A.H. et al. Cloning and characterization of two human skeletal muscle α-actinin genes located on chromosomes 1 and 11. J. Biol. Chem. 267, 9281–9288 (1992).

    CAS  PubMed  Google Scholar 

  13. Wachsstock, D.H., Schwartz, W.H. & Pollard, T.D. Affinity of α-actinin for actin determines the structure and mechanical properties of actin filament gels. Biophys. J. 65, 205–214 ( 1993).

    Article  CAS  Google Scholar 

  14. Drenckhahn, D., Schnittler, H., Nobiling, R. & Kriz, W. Ultrastructural organization of contractile proteins in rat glomerular mesangial cells. Am. J. Pathol. 137, 1343– 1351 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Eilertsen, K.J., Kazmierski, S.T. & Keller, T.C. III Interaction of α-actinin with cellular titin . Eur. J. Cell. Biol. 74, 361– 364 (1997).

    CAS  PubMed  Google Scholar 

  16. Carpen, O., Pallai, P., Staunton, D.E. & Springer, T.A. Association of intercellular adhesion molecule-1 (ICAM-1) with actin-containing cytoskeleton and α-actinin. J. Cell Biol. 118 , 1223–1234 (1992).

    Article  CAS  Google Scholar 

  17. Papa, I. et al. α-actinin-CapZ, an anchoring complex for thin filaments in Z-line. J. Muscle Res. Cell Motil. 20, 187–197 (1999).

    Article  CAS  Google Scholar 

  18. Fukami, K., Endo, T., Imamura, M. & Takenawa, T. α-Actinin and vinculin are PIP2-binding proteins involved in signaling by tyrosine kinase . J. Biol. Chem. 269, 1518– 1522 (1994).

    CAS  PubMed  Google Scholar 

  19. Sampath, R., Gallagher, P.J. & Pavalko, F.M. Cytoskeletal interactions with the leukocyte integrin β2 cytoplasmic tail. Activation-dependent regulation of associations with talin and α-actinin. J. Biol. Chem. 273, 33588–33594 (1998).

    Article  CAS  Google Scholar 

  20. Reinhard, M. et al. An α-actinin binding site of zyxin is essential for subcellular zyxin localization and α-actinin recruitment. J. Biol. Chem. 274, 13410–13418 (1999).

    Article  CAS  Google Scholar 

  21. Pomies, P., Louis, H.A. & Beckerle, M.C. CRP1, a LIM domain protein implicated in muscle differentiation, interacts with α-actinin. J. Cell Biol. 139, 157–168 (1997).

    Article  CAS  Google Scholar 

  22. Shih, N.Y. et al. Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286, 312– 315 (1999).

    Article  CAS  Google Scholar 

  23. Holzman, L.B. et al. Nephrin localizes to the slit pore of the glomerular epithelial cell. Kidney Int. 56, 1481– 1491 (1999).

    Article  Google Scholar 

  24. Mathis, B.J., Calabrese, K.E. & Slick, G.L. Familial glomerular disease with asymptomatic proteinuria and nephrotic syndrome: a new clinical entity. J. Am. Osteopath. Assoc. 92, 875–884 ( 1992).

    Article  CAS  Google Scholar 

  25. Tomero, J.S. et al. Focal segmental glomerulosclerosis in three generations of a single family. Int. J. Pediatr. Nephrol. 6, 199–204 (1985).

    Google Scholar 

  26. Ausubel, R.M. et al. Current Protocols in Molecular Biology (Greene, New York, 1995).

    Google Scholar 

  27. North, K.N. & Beggs, A.H. Deficiency of a skeletal muscle isoform of α-actinin (α-actinin-3) in merosin-positive congenital muscular dystrophy. Neuromuscul. Disord. 6, 229–235 (1996).

    Article  CAS  Google Scholar 

  28. North, K.N. et al. A common nonsense mutation results in α-actinin-3 deficiency in the general population. Nature Genet. 21, 353–354 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the family members for participation; members of the Department of Genetics, Harvard Medical School and the Department of Medicine at Brigham and Women's Hospital, particularly B. Denker, for helpful discussions; A. Shahsafaei for help with immunofluorescence; L. Ashworth for help with chromosome 19 sequence informatics; M. Dolliver for help with clinical ascertainment; and members of the core sequencing facilities and the Genome Center at the Brigham and Women's Hospital for their assistance. This work was supported by NIH grants DK54931 (M.R.P.), AR44345 and AR02026 (A.H.B.), GM57256 (P.G.A.) and a National Research Service Award (J.M.K.), as well as grants from the National Kidney Foundation and the Burroughs Wellcome Fund (M.R.P.) and the Muscular Dystrophy Association (A.H.B.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin R. Pollak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaplan, J., H Kim, S., North, K. et al. Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24, 251–256 (2000). https://doi.org/10.1038/73456

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/73456

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing